A sponsor of a significant risk device study must submit a complete IDE application to FDA. There are no preprinted forms for an IDE application; however, an IDE application must include certain required information. The sponsor must demonstrate in the application that there is reason to believe that the risks to human subjects from the proposed investigation are outweighed by the anticipated benefits to subjects and the importance of the knowledge to be gained, that the investigation is scientifically sound, and that there is reason to believe that the device as proposed for use will be effective.

Required Elements

The following information must be included in an IDE application for a significant risk device investigation. A sponsor cannot begin a significant risk device investigation until FDA and IRB approval are granted. Three copies of a signed IDE application are required and the application must include the following in the order provided (§ 812.20):

Name and address of sponsor

Report of prior investigations (§ 812.27). A report of prior investigations must include reports of all prior clinical, animal, and laboratory testing of the device. It should be comprehensive and adequate to justify the proposed investigation. Specific contents of the report must include:

a bibliography of all publications, whether adverse or supportive, that are relevant to an evaluation of the safety and effectiveness of the device

copies of all published and unpublished adverse information

copies of other significant publications if requested by an IRB or FDA

a summary of all other unpublished information (whether adverse or supportive) that is relevant to an evaluation of the safety and effectiveness of the device

if nonclinical laboratory data are provided, a statement that such studies have been conducted in compliance with the Good Laboratory Practice (GLP) regulations in 21 CFR Part 58. If the study was not conducted in compliance with the GLP regulations, include a brief statement of the reason for noncompliance.

Investigational plan (§812.25)

The investigational plan shall include the following items in the following order:

purpose (the name and intended use of the device and the objectives and duration of the investigation)

protocol (a written protocol describing the methodology to be used and an analysis of the protocol demonstrating its scientific soundness)

risk analysis (a description and analysis of all increased risks to the research subjects and how these risks will be minimized; a justification for the investigation; and a description of the patient population including the number, age, sex, and condition)

description of this device (a description of each important component, ingredient, property, and principle of operation of the device and any anticipated changes in the device during the investigation)

monitoring procedures (the sponsor's written procedures for monitoring the investigation and the name and address of each monitor.

additional records and reports (a description of any records or reports of the investigation other than those required in Subpart G of the IDE regulations).

A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and installation of the device

An example of the agreement to be signed by the investigators and a list of the names and addresses of all investigators. Information that must be included in the written agreement are found in § 812.43

Certification that all investigators have signed the agreement, that the list of investigators includes all investigators participating in the study, and that new investigators will sign the agreement before being added to the study

A list of the names, addresses, and chairpersons of all IRBs that have or will be asked to review the investigation and a certification of IRB action concerning the investigation (when available)

The name and address of any institution (other than those above) where a part of the investigation may be conducted

The amount, if any, charged for the device and an explanation of why sale does not constitute commercialization

Please note that an environmental assessment as required under 21 CFR 25.40 or a claim for categorical exclusion under 21 CFR 25.30 or 25.34 is no longer required. [§25.34(g)]

Copies of all labeling for the device

Copies of all informed consent forms and all related information materials to be provided to subjects as required by 21 CFR 50, Protection of Human Subjects

Any other relevant information that FDA requests for review of the IDE application. Information previously submitted to FDA in accordance with Part 812 may be incorporated by reference.

Suggested Content for Original IDE Application Cover Letter

It is recommended that the cover letter include the following information in the order provided to assist in the administrative processing of the application.

Statement that the information provided is an original IDE submission.

Device Information:

Device Name

Intended Use

Sponsor contact information:

Name

Address

Contact Person

Telephone Number

Fax

Email address

Please note that the sponsor MUST be located in United States [21 CFR 812.18(a)].

Manufacturer Information:

Name

Address

Contact Person

Telephone Number

Fax

Correspondent Information: If the organization submitting the application is not the sponsor, such as a consultant or a lawyer, include contact information for the correspondent organization or individual.

Provide the following information, if applicable: Pre-Submission/Pre-Submission meetings: Describe any discussions with the FDA reviewing division regarding this device. If a Pre-Submission (Pre-Sub) was submitted, state the Pre-Sub number and a copy of the written feedback provided by. If a Pre-Sub meeting occurred, provide the name of the FDA contact person and a copy of the meeting minutes.

Waiver Requests: Identify any requests for waivers and include a justification for the waiver.

Referenced Files: Identify any files that are referenced in the IDE application, such as Premarket Approval, Premarket Notification 510(k), IDE, or device master files. If files were not submitted by the sponsor, include a letter from the owner of the files that grants FDA permission to reference the files in its review of the current application.

Suggested Format for IDE Submissions

In order to facilitate FDA's handling of IDE applications, the following recommendations are offered:

Use paper with nominal dimensions of 8 1/2" by 11".

Use at least a 1 1/2" wide left margin to allow for binding into jackets.

Use 3-hole punched paper to allow for binding into jackets.

If the submission exceeds 2" in thickness, separate into volumes and identify volume number.

Clearly and prominently identify submission as original IDE application or, for additional submissions to an IDE application, clearly identify the FDA assigned document number (e.g., G960000) and the reason for the submission (e.g., amendment, supplement, or report) and the type of submission (e.g., Response to FDA letter; Addition of New Institution, etc.).

Do not combine IDEs, PMAs and 510(k)s together; they must be separate submissions.

Unless the IDE sponsor has provided authorization in writing for another person to submit information on the sponsor's behalf, only the IDE sponsor may amend, supplement, or submit reports to the IDE.

Sequentially number the pages, providing a detailed table of contents, and use tabs to identify each section. This will help to facilitate the review of your submission.

Common Problems with Original IDE Applications

The sponsor should assure that the device, all preclinical testing, and the investigational plan are described and provide adequate justification for the initiation of the clinical trial. Submitters should avoid submitting the IDE application prematurely. There are three common areas that are frequently deficient in IDE applications.

Inadequate report of prior investigations

Inadequate investigational plan

Inadequate/incomplete design and manufacture

Common deficiencies with report of prior investigations

A report of prior investigations must include reports of all prior clinical, animal, and laboratory testing of the device. It should be comprehensive and adequate to justify the proposed investigation.

Common deficiencies with investigational plan

investigational plan includes elements that would expose study subjects to unacceptable probable risks

failure to develop proper monitoring procedures

inadequate informed consent documents

Common deficiencies with design and manufacturing

design: Inadequate characterization or description of the device and its operation due to inadequate or omitted:

Design/engineering drawing of device

Rationale for device design

Device and performance specifications

Description of materials (including biocompatibility information)

Description of function - how does device and/or components/subsystems work together to achieve desired function

Validation testing for subsystems and main system

manufacturing: Inadequate or missing description of the controls used to ensure that the devices are produced consistently and as designed.

Suggested Original IDE Application Administrative Checklist

Following is a suggested checklist that submitters may use to ensure that their original IDE application is administratively complete. The first section is a screening to determine whether an IDE application is required to be submitted to FDA. The next section is the information suggested to be included in the cover letter or cover page of the IDE application. Inclusion of this information should help speed FDA's administrative processing of the application. The last section is a checklist to ensure that all the information required by regulation is addressed in the application.

Screening Information - Is an IDE application to FDA necessary?

Is the investigation within the categories exempt from the IDE regulation under §812.2(c)?(If yes, stop. IDE application is not required. IRB clearance and informed consent is recommended; please check institution's policies.)

Yes/No

Is this a nonsignificant risk device investigation?(If yes, stop. Submission to and approval from FDA is not required for nonsignificant risk devices. Follow abbreviated requirements (§812.2(b)) including IRB approval and informed consent.)

Yes/No

If the answer to both of these questions is no, an IDE application must be submitted to FDA and approval must be obtained from both FDA and the IRB before the study may begin

Checklist for Cover Letter

Element

Included

Statement that submission is an original IDE application.

Yes/No

Device Information:

Device Name

Intended Use

Yes/No

Sponsor – (must be located in United States) [§812.18(a)]:

Name

Address

Contact Person

Telephone Number

Fax

Email address

Yes/No

Manufacturer Information

Name

Address

Contact Person

Telephone Number

Fax

Yes/No

Correspondent Information (Note: IDE application will not be approved without a U.S. sponsor) [§812.18(a)]

Checklist for an IDE Application

Are the following items provided and are they comprehensive and adequate to justify the proposed investigation?

Report of all prior clinical, animal and laboratory testing

Yes/No

Bibliography of all publications, whether adverse or supportive, that are relevant to an evaluation of the safety and effectiveness of the device

Yes/No

Copies of all published and unpublished adverse information

Yes/No

Summary of all other unpublished information, whether adverse or supportive, that is relevant to an evaluation of safety and effectiveness of the device

Yes/No

Statement whether nonclinical tests comply with the good laboratory practice (GLP) regulations in Part 58

If any studies were not conducted in compliance with the GLP regulation, a brief statement of the reason for the noncompliance must be provided. Failure or inability to comply with this requirement does not justify failure to provide information on a relevant nonclinical test study.

Yes/No

If any item is not provided, a justification for its omission must be provided.

Investigational Plan (§ 812.25):

Are the following items included, preferably in the following order:

Purpose: Are the following clearly defined?

name and intended use of the device

objectives of the investigation

duration of the investigation (specify in months and years)

Yes/No

Protocol: Are the following items provided and adequate?

a written protocol describing the methodology to be used including:

objectives, hypothesis to be tested, or question to be answered

description of the type of trial (i.e., controlled/open, double-blind/single-blind, etc.)

detailed description of the conduct of the trial

description of statistical methods

case report forms

an analysis of the protocol demonstrating its scientific soundness

Yes/No

Risk Analysis: Are the following items provided and adequate to determine that the benefit and knowledge to be gained from the investigation outweigh the risks to the subjects?

a description and analysis of all increased risks to the research subjects

the manner in which risks will be minimized

a justification for the investigation

a description of patient population, including number, age, sex and condition

Yes/No

Description of the Device: Are the following items provided and adequate?

a description of each important component, ingredient and property

the principle of operation of the device

a description of any anticipated changes in the device during the investigation

Yes/No

Monitoring Procedures: Are the following items present?

the written procedure for monitoring the investigation

the name and address of the individual(s) who will monitor the study

Yes/No

Manufacturing Information: [812.20(b)(3)]

Is adequate manufacturing information provided to allow a judgement about the quality control of the device (e.g., that the device will meet the intended specifications) based on the description of methods, facilities and controls used for:

where applicable, a statement of the investigator's relevant experience (including the dates, location, extent and type of experience);

if the investigator was involved in an investigation or other research that was terminated, an explanation of the circumstances that led to termination; and

a statement of the investigator's commitment to:

conduct the investigation in accordance with the agreement, the investigational plan, Part 812 and other applicable FDA regulations, and conditions of approval imposed by the reviewing IRB and FDA;

supervise all testing of the device involving human subjects; and

ensure that the requirements for obtaining informed consent are met

Investigator’s commitment to provide sufficient and accurate financial disclosure information and update information if any relevant changes occur during the investigation and for one year following the completion of the study.

Yes/No

Certification that all participating investigators have signed the agreement and that no investigator will be added until the agreement is signed. [812.20(b)(5)]

Yes/No

Name and address of investigators who have signed the agreement.

Yes/No

IRB Information:

Are the following items included?

Name, address, and chairperson of each IRB

Yes/No

Certification of the action taken by each IRB, (i.e., approval letter)

How many IRBs have approved the investigation?

How many IRBs are currently reviewing the investigation or will review it in the future?

Yes/No

Names and addresses of any institutions (other than those identified above) where a part of the investigation may be conducted

Yes/No

Sales Information: [812.7(b)]

Is the following information provided?

Is the device to be sold?

Yes/No

If yes, is the amount to be charged provided?

Yes/No

Explanation of why sale does not constitute commercialization

Yes/No

§ 812.7(b) prohibits the commercialization of an investigational device by charging subjects or investigators for a device a price larger than necessary to recover costs of manufacture, research, development, and handling.

Environmental Impact Assessment: [§812.20(b)(9)]

An environmental impact assessment or a claim for categorical exclusion is no longer required. [§25.34(g)]

Labeling: [§812.5] Are copies of all labeling for the device provided and include the following?

Does the labeling contain the statement "CAUTION-Investigational Device. Limited by Federal (or United States) Law to Investigational Use." [§ 812.5(a))]

Yes/No

Does the labeling contain adequate information for the purposes of the investigation, in accordance with § 812.5(a), including the name and place of business of the manufacturer, packer, or distributor, the quantity of contents, and a description of all relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings, and precautions?

If any item is not addressed, a justification for its omission must be provided.

Yes/No

Note: The device may not be promoted as safe and effective for the use for which it is being investigated. [§812.7(d)]

Informed Consent Materials: [21 CFR 50, 812.25(g)]

Are all forms and informational materials to be presented to the subject included?

Yes/No

Does the informed consent form seek consent from the subject or a legally authorized representative, when appropriate (e.g., when the subject is a minor)?

a description of any reasonably foreseeable risks or discomforts to the subject

a description of any benefits to the subject or others

a disclosure of appropriate alternative procedures or courses of treatment that might be advantageous to the subject

a statement describing the extent to which confidentiality of the subject's records will be maintained and that FDA may inspect the records

an explanation as to whether any compensation and/or medical treatments are available if injury occurs and, if so, what they consist of or sources of further information

an explanation of whom to contact for answers to questions about the study and the subject's rights and whom to contact in the event of a research-related injury

a statement that participation is voluntary and that subjects may refuse to participate or discontinue participation at any time without penalty or loss of benefits

Yes/No

Additional Elements Required When Justified:

A statement that the procedure or treatment may involve unforeseeable risks to subject, or to the embryo or fetus if the subject were to become pregnant

Anticipated circumstances under which the investigator may terminate the subject's participation without regard to the subject's consent

Any additional costs to subject as a result of participation

Consequences of a subject's decision to withdraw and procedures for withdrawal

A statement that significant new findings which may relate to the subject's willingness to participate will be provided to the subjects

The approximate number of subjects involved in the study

Does the consent process involve a "short form" written consent [21 CFR Part 50.27(b)(2))]. If yes, a copy of the "short form" and a written summary of what is to be said to the subject or representative should be provided.

Yes/No/NA

The informed consent form may not contain exculpatory language [21 CFR Part 50.20]

Other Information:

Provide additional information supportive of the investigation and any information FDA has identified (through previous contact with the agency or through guidance documents) as required.

If any item is not provided, a justification for its omission must be provided.

Address for IDE Applications

Sponsors of a significant risk device investigation must submit three copies of a signed "Application for Investigational Device Exemption." That is, the cover page of your application should identify the submission as an application for investigational device exemption and the page should be signed by the sponsor. There are no IDE application forms. For most devices, mail the cover page and accompanying materials, including a valid eCopy, to the following address:

All correspondence relating to an IDEs regulated by CDRH should also be sent to this address. The IDE correspondence should be submitted in triplicate and reference the IDE number. The outside wrapper of each submission should identify the contents, for example, "Original IDE Application," " IDE Supplement," "IDE Report," etc.

Devices regulated by the Center for Biologics Evaluation and Research (CBER):

IDE Modifications

A sponsor must obtain approval of a supplemental application and IRB approval (when appropriate under conditions described in §56.110 and §56.111 prior to implementing a change to an investigational plan except in situations described below. If a sponsor intends to conduct an investigation that involves an exception to informed consent under §50.24 (see Informed Consent), the sponsor must submit a separate investigational device exemption (IDE) application [§812.20(a)].

The IDE supplement should be identified with the IDE number on the cover sheet and submitted in duplicate with a valid eCopy. The outside wrapper of the submission should identify the contents as an "IDE Supplement."

Changes that do not require prior FDA approval.

The sponsor of an IDE may modify the device and/or clinical protocol without approval of a new IDE application or IDE supplement if the modifications meet certain criteria. The notice must be provided to FDA within 5 working days of making the change.

Emergency UseFDA approval of a supplement does not apply in the case of a deviation from the investigational plan to protect the life or physical well-being of a subject in an emergency. However, such deviation must be reported to FDA within 5-working days after the sponsor learns of it [§812.150(a)(4)]. Additional information can be found in "Guidance on IDE Policies and Procedures"

Certain Developmental Changes

Criteria: An FDA approved IDE supplement is not required for developmental changes in the device (including manufacturing changes) that do not constitute a significant change in design or basic principles of operation and that are made in response to information gathered during the course of an investigation. This determination is made by the sponsor and must be based on credible information. Credible information to support developmental changes in the device (including manufacturing changes) includes data generated under the design control procedures of §820.30, preclinical/animal testing, peer reviewed published literature, or other reliable information such as clinical information gathered during a trial or marketing. The sponsor must provide notice to FDA within 5-working days of making these changes.

Generic types of device and manufacturing changes include changes to the control mechanism, principle of operation, energy type, environmental specifications, performance specifications, ergonomics of patient-user interface, dimensional specifications, software or firmware, packaging or expiration dating, sterilization, and the manufacturing process (including the manufacturing site). Any specific change within a particular type may or may not be appropriate under the 5-day notice provision because changes in each of these categories could range from minor to significant depending upon the particular device, the type of modification, and the extent of the modification. The impact of the change would still need to be determined by information generated by design controls or other appropriate means to assess the significance of the change to the device design or manufacturing process and the appropriateness of a 5-day notice submission.

Please note that all developmental changes need to be reported to the IRB in the sponsor’s annual report. In addition, the changes may be subject to IRB review procedures under 21 CFR 56.110.

All changes to the basic principles of operation of a device are considered to be significant changes that should be submitted in an IDE supplement.

5-day Notice: The sponsor must submit a notice of the change to the IDE no later than 5-working days after making the change. Changes to devices are deemed to occur on the date the device, manufactured incorporating the design or manufacturing change, is distributed to the investigator(s). These notices must be identified as a "notice of IDE change.''

For a developmental or manufacturing change to the device, the notice must include a summary of the relevant information gathered during the course of the investigation upon which the change was based; a description of the change to the device or manufacturing process (cross-referenced to the appropriate sections of the original device description or manufacturing process); and, if design controls were used to assess the change, a statement that no new risks were identified by appropriate risk analysis and that the verification and validation testing, as appropriate, demonstrated that the design outputs met the design input requirements. If another method of assessment was used, the notice must include a summary of the information which served as the credible information supporting the change. FDA will only notify the sponsor if questions arise or additional information is needed.

Certain changes to the clinical protocol

Criteria: An FDA approved IDE supplement is not required for changes to clinical protocols that do not affect:

The validity of the data or information in the approved protocol, or the patient risk to benefit relationship relied upon to approve the protocol

The scientific soundness of the investigational plan

The rights, safety, or welfare of the human subjects involved in the investigation.

This determination is made by the sponsor and must be based on credible information. Credible information to support changes to clinical protocols is defined as the sponsor's documentation supporting the conclusion that a change does not have a significant impact on the study design or planned statistical analysis, and that the change does not affect the rights, safety, or welfare of the subjects. Documentation must include information such as peer reviewed published literature, the recommendation of the clinical investigator(s), and/or the data gathered during the clinical trial or marketing. The sponsor must provide notice to FDA within 5 working days of making these changes.

Examples of these types of changes may include the following changes:

Modification of inclusion/exclusion criteria to better define the target patient population

Increasing the frequency at which data or information is gathered

Inclusion of additional patient observations or measurements

Modifying the secondary endpoints (Secondary endpoints usually support a secondary labeling claim that the sponsor wants to make for the device and are not used to determine the safety or effectiveness of the device.)

5-day Notice

The sponsor must submit a notice of the change to the IDE no later than 5 working days after making the change. Changes to a clinical protocol are deemed to occur when a clinical investigator is notified by the sponsor that the change should be implemented in the protocol or, for sponsor-investigator studies, when a sponsor-investigator incorporates the change in the protocol. These notices must be identified as a "notice of IDE change."

For a protocol change, the notice must include a description of the change (cross-referenced to the appropriate sections of the original protocol); an assessment supporting the conclusion that the change does not have a significant impact on the study design or planned statistical analysis; and a summary of the information that served as the credible information supporting the sponsor's determination that the change does not affect the rights, safety, or welfare of the subjects. FDA will only notify the sponsor if questions arise or additional information is needed.

Changes to be submitted in the annual report

Minor changes in the following areas:

the purpose of the study

risk analysis

monitoring procedures

labeling

informed consent materials

IRB information

may be reported in the annual progress report for the IDE if the changes do not affect:

the validity of the data or information resulting from the completion of the approved protocol or the relationship of likely patient risk to benefit relied upon to approve the protocol

the scientific soundness of the investigational plan

the rights, safety, or welfare of the human subjects involved in the investigation [812.150(b)(5)]

If the changes do affect the above criteria, then prior approval must be obtained.

IDE supplements for new facilities

FDA will review initial IDE applications that do not contain a certification of IRB approval for each site. FDA may approve the investigational sites without IRB approval. The sponsor is required to submit the certification in an IDE supplement when he obtains IRB approval. If the site is already approved and the supplement is just the certification of IRB approval, FDA usually does not provide a written response to the certification since the site has previously been approved by FDA.

If the sponsor has determined the number of investigational sites for the study but not yet identified all the sites at the time the IDE is submitted, FDA may grant a waiver to the sponsor. The waiver would allow the sponsor to enroll the sites, obtain IRB approvals, and then submit all the certifications of IRB approval to FDA at one time (or at 6 month intervals if it takes that long to enroll the sites) instead of requesting each site as it is identified.

Once the IDE is approved, the sponsor may submit an IDE supplement to request approval of additional clinical study sites. FDA will respond in writing to the supplement approving or denying the request. The sponsor is required to submit;